It is generally recognized that many disease processes are attributed to the presence of elevated levels of free radicals and reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as superoxide, hydrogen peroxide, singlet oxygen, peroxynitrite, hydroxyl radicals, hypochlorous acid (and other hypohalous acids) and nitric oxide.
In the eye, cataract, macular degeneration and degenerative retinal damage are attributed to ROS. Among other organs and their ROS-related diseases include: lung cancer induced by tobacco combustion products and asbestos; accelerated aging and its manifestations, including skin damage and scleroderma; atherosclerosis; ischemia and reperfusion injury, diseases of the nervous system such as Parkinson disease, Alzheimer disease, muscular dystrophy, multiple sclerosis; lung diseases including emphysema and bronchopulmonary dysphasia; iron overload diseases such as hemochromatosis and thalassemia; pancreatitis; diabetes; renal diseases including autoimmune nephrotic syndrome and heavy metal-induced nephrotoxicity; and radiation injuries. Diseases of aging and chronic emotional stress also appear to be associated with a drop in glutathione levels, which allows ROS to remain active.
Certain anti-neoplastic drugs such as adriamycin and bleomycin induce severe oxidative damage, especially to the heart, limiting the patient's exposure to the drug. Redox-active metals such as iron induce oxidative damage to tissues; industrial chemicals and ethanol, by exposure and consumption, induce an array of oxidative damage-related injuries, such as cardiomyopathy and liver damage. Airborne industrial and petrochemical-based pollutants, such as ozone, nitric oxide, radioactive particulates, and halogenated hydrocarbons, induce oxidative damage to the lungs, gastrointestinal tract, and other organs. Radiation poisoning from industrial sources, including leaks from nuclear reactors and exposure to nuclear weapons, are other sources of radiation and radical damage. Other routes of exposure may occur from living or working in proximity to sources of electromagnetic radiation, such as electric power plants and high-voltage power lines, x-ray machines, particle accelerators, radar antennas, radio antennas, and the like, as well as using electronic products and gadgets which emit electromagnetic radiation such as cellular telephones, and television and computer monitors.
Mammalian cells have numerous mechanisms to eliminate these damaging free radicals and reactive species. One such mechanism includes the glutathione system, which plays a major role in direct, destruction of reactive oxygen compounds.
Perhaps one of the most important contributions of glutathione to mammalian health is its participation in the proper functioning of the immune system to respond to infection or other types of trauma. It is known that weakening of the immune system caused by infection or other traumas occurs concurrently with depletion of glutathione in body tissues. It is known, also, that such weakening can be reversed by replenishing the body's level of glutathione by intracellular synthesis. It is believed that glutathione accomplishes its salutary effects by protecting immune cells against the ravages of oxidizing agents and free radicals.
Until recently, the lack of specific and dependable methods for evaluating oxidant stress in vivo made it very difficult to establish a cause and effect relationship between free radical-generating agents or conditions and disease pathology. Furthermore, the various treatment strategies with anti-oxidants have been difficult to monitor due to the lack of techniques sufficiently sensitive to reliably provide an index of oxidative damage in vivo.
For example, there is currently substantial evidence that oxidation of LDL occurs in vivo, and results of animal studies suggest that this may lead to the formation and build up of atherosclerotic plaques. Although epidemiological data support a role for antioxidants in the prevention of clinical events, intervention trials thus far have given mixed results (Steinberg D, Witztum J L. Lipoproteins, lipoprotein oxidation, and atherogenesis. In Chien K R, ed. Molecular Basis of Cardiovascular Disease. Philadelphia, Pa.: W.B. Saunders Co., 1998:458-475). This may be due, in part, to the fact that until now techniques to adequately provide an index of in vivo lipid peroxidation have not been available, which could be used to design and monitor effective antioxidant intervention trials to adequately test the oxidation hypothesis.
Furthermore, there are no set measures to identify high-risk groups that would theoretically benefit most from antioxidant therapies or interventions. Additionally, there are no reliable means to measure or determine the effectiveness of such interventions in vivo. In the absence of such methodology, current (and future) clinical trials testing natural (or synthetic) antioxidants, which utilize clinical endpoints, may give incorrect conclusions regarding the role of antioxidants in specific disease states. This is a possibility because of the inclusion of populations that would not be expected to benefit from antioxidant supplementation, and/or because the dose or agent yielded insufficient antioxidant protection.
It is with respect to the development of more sensitive and accurate assays for assessing the need for intervention with anti-oxidant therapy and for monitoring the effectiveness and utilization efficiency of novel anti-oxidants that the current invention is directed.